Daclatasvir plus peginterferon and ribavirin is noninferior to peginterferon and ribavirin alone, and reduces the duration of treatment for HCV genotype 2 or 3 infection.

BACKGROUND & AIMS: Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy. METHODS: Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24). RESULTS: Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those expected from peginterferon alfa and ribavirin therapy. CONCLUSIONS: Twelve or 16 weeks of treatment with daclatasvir, in combination with peginterferon alfa-2a and ribavirin, is a well tolerated and effective therapy for patients with HCV genotype 2 or 3 infections. Daclatasvir-containing regimens could reduce the duration of therapy for these patients. Clinicaltrials.gov number: NCT01257204.

Effects of ribavirin dose reduction vs erythropoietin for boceprevir-related anemia in patients with chronic hepatitis C virus genotype 1 infection--a randomized trial.

BACKGROUND & AIMS: Treatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety. METHODS: Patients (n = 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251). RESULTS: Rates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total milligrams of ribavirin assigned by the protocol had a significantly lower rate of SVR (P < .0001) than those who received ≥50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported in 9 of 295 patients who received erythropoietin, compared with 1 of 392 patients who did not receive erythropoietin. CONCLUSIONS: Reduction of ribavirin dosage can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dosage throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (milligrams) of ribavirin assigned by response-guided therapy. ClinicalTrials.gov number, NCT01023035.

Directly observed pegylated interferon plus self-administered ribavirin for the treatment of hepatitis C virus infection in people actively using drugs: a randomized controlled trial.

BACKGROUND: This study investigated the efficacy and safety of directly observed pegylated interferon (peg-IFN) alfa-2a plus self-administered ribavirin (RBV) for the treatment of hepatitis C virus (HCV) among people with active drug use. METHODS: A randomized, open-label, parallel group trial of immediate vs delayed treatment with peg-IFN alfa-2a plus RBV in participants with recent injection drug and/or crack cocaine use (prior 3 months). The primary end point was sustained virologic response (SVR). RESULTS: Sixty-six participants were randomized (immediate treatment, n = 48; delayed treatment, n = 18). Loss to follow-up was comparable among those randomized to immediate and delayed treatment (23% vs 33%, P = .389). In a post hoc intent-to-treat analysis of all randomized individuals, the SVR was 65% (95% confidence interval [CI], 49%-78%; 31/48) in those randomized to immediate treatment as compared to 39% (95% CI, 17%-64%; 7/18) in those randomized to delayed treatment (P = .060). Among those who received delayed treatment (12/18), SVR was 58% (7/12). Among 60 participants who received at least 1 dose of study medication, SVR was 63% (95% CI, 50%-75%, n = 38). Recent drug use at baseline (past month) did not impact completion or SVR. Discontinuation due to adverse events occurred in 7%. The HCV reinfection rate was 2.8 per 100 person-years (95% CI, 0.0-14.5 person-years) with 1 reinfection observed among 23 remaining in follow-up post-SVR (median, 1.8 years; range, 0.5-1.8 years). CONCLUSIONS: Among people actively using drugs treated with directly observed peg-IFN alfa-2a plus self-administered RBV, SVR is comparable to that seen in clinical trials of non-drug users, and the rate of HCV reinfection is low.

How to optimize HCV therapy in genotype 1 patients: management of side-effects.

Antiviral therapy for chronic hepatitis C has dramatically changed with the advent of triple therapy incorporating direct-acting antivirals (DAAs) such as the protease inhibitors (PI) boceprevir and telaprevir. Such triple-therapy is associated with a new spectrum of side-effects which can hamper quality of life. These may lead to dosage reduction and sometimes discontinuation of therapy. This review presents practical tips to help manage adverse effects appropriately and efficiently. The main adverse effects causing discontinuation of therapy are varied. Although the most common adverse effects are the 'flu'-like symptoms of fatigue, myalgia, fever and lassitude, these are usually easily managed and do not lead to treatment discontinuation. Cytopaenia, particularly anaemia, has emerged as perhaps the most troublesome side-effect. Cirrhotic patients are especially prone to moderate or severe anaemia with boceprevir and telaprevir triple-therapy regimens. Aggressive ribavirin dosage reductions, erythropoietin and blood transfusions are effective for managing anaemia. Skin rash can be controlled with moisturization and corticosteroid ointment. Rarely, dermatology consultation is required for further management. Anal discomfort, with or without diarrhoea, sometimes responds to barrier creams and haemorrhoidal ointments. Dysgeusia is treated by sipping water frequently, oral ointments and mouth washes to maintain salivary flow and oral hygiene. Successful adherence to treatment can be enhanced by a strong support network for the patient, including specially-trained hepatitis nurses and a multidisciplinary team incorporating pharmacists, counsellors and social workers.

Safety of peginterferon alfa-2a plus ribavirin in a large multinational cohort of chronic hepatitis C patients.

BACKGROUND & AIMS: Peginterferon plus ribavirin has been the standard of care for chronic hepatitis C for a decade and an essential component of combination regimens for this disease. This large multinational open-label study aimed to better define the incidence of serious adverse events (SAEs) and non-serious adverse events of special interest in patients receiving peginterferon alfa-2a/ribavirin. METHODS: Patients were assigned at the investigator's discretion to 24- or 48-week treatment with peginterferon alfa-2a 180 µg/week and ribavirin 800 mg/day or 1000/1200 mg/day. All AEs, defined as SAEs and non-SAEs of special interest, were recorded during treatment and for 12 weeks thereafter. Non-SAEs of special interest included those leading to dose reduction/discontinuation, neutropenia, thrombocytopenia, anaemia, ALT elevations leading to dose modification and unknown/unexpected AEs. RESULTS: Of 1675 and 7178 patients assigned to 24 and 48 weeks of treatment, respectively, 87.6 and 68.3% completed therapy, whereas 6.4 and 10.3% prematurely stopped peginterferon alfa-2a treatment because of AEs. Among patients assigned to 24 and 48 weeks, 37.4 and 46.9%, respectively, reported any AE (SAE or non-SAE of special interest); 4.2 and 6.6% reported SAEs and 35.2 and 44.0% reported non-SAEs of special interest. Female gender, increasing age and cirrhosis were significantly associated with dose reductions of either drug. Increasing age (and female gender in the case of ribavirin) was significantly associated with treatment discontinuation. CONCLUSION: This study confirmed the safety and tolerability profile of peginterferon alfa-2a/ribavirin and identified patient subgroups at higher risk of dose reductions and discontinuations, thus allowing optimum management of AEs.

Is pre-treatment liver biopsy necessary for all hepatitis C genotypes?

BACKGROUND: Current practice guidelines recommend liver biopsy prior to treatment of hepatitis C genotype-1 but not for genotype-2/3; this is based on expert opinion, not on published evidence. METHODS: In retrospective analysis of a large trial database prior to the publication of recent guidelines, we compared outcomes in 985 treatment-naïve patients with hepatitis C who did or did not undergo liver biopsy before starting peginterferon alfa-2a plus ribavirin. RESULTS: Physicians elected to treat 141/654 (21.6%) genotype-1 patients and 126/331 (38.1%) genotype-2/3 patients without liver biopsy. There were no differences in baseline characteristics among those with or without pre-treatment liver biopsy, except for female preponderance in genotype-1 patients with liver biopsy. The sustained viral response (SVR) rate was no different amongst genotype-2/3 patients who had a biopsy before treatment with 66.3% SVR vs. 69.8% of those treated without biopsy (p = 0.546), but significantly higher among genotype-1 patients with pre-treatment liver biopsy at 54.6 vs. 44.0% for those treated without a liver biopsy (p = 0.029). In genotype-1 patients with liver biopsy, more patients with cirrhosis had dose adjustments (p = 0.0057) rather than drug discontinuation. There was tendency for earlier discontinuation among patients without pre-treatment liver biopsy. CONCLUSIONS: Pre-treatment liver biopsy was associated with better SVR amongst genotype-1 patients. This improvement may reflect ongoing commitment to completing the treatment course by both patient and physician. In genotype-2/3 patients, pre-treatment liver biopsy may not be essential to maximize SVR rates. This study validates the recommendations of the most recent treatment guidelines for hepatitis C.

Optimizing outcomes in patients with hepatitis C virus genotype 1 or 4.

Currently, many decisions for the treatment of hepatitis C virus (HCV) are based on genotype, which is the most significant baseline predictor of response to therapy; however, it has become increasingly apparent that fixed treatment durations might not be appropriate for all patients. The use of on-treatment predictors such as rapid virological response (RVR) at week 4 and early virological response (EVR) at week 12 can be used to predict the likelihood of achieving a sustained virological response (SVR), helping to tailor treatment to the individual. Until now, EVR has been defined as achieving either undetectable HCV RNA (< 50 IU/ml) or a > 2 log drop in HCV RNA, but still detectable, at week 12. However, rates of SVR in patients achieving an EVR are heterogeneous. It has recently been suggested that by subdividing EVR into RVR (< 50 IU/ml at week 4), complete EVR (HCV RNA < 50 IU/ml at week 12) or partial EVR (HCV RNA > 2 log drop in HCV RNA but still detectable [> 50 IU/ml] at week 12), it might be possible to further improve the prediction of patients likely to achieve an SVR and may allow for tailoring of treatment duration. Genotype 1 and 4 patients achieving an RVR have high rates of SVR and may be candidates for shorter treatment duration. Patients with a complete EVR achieve high SVR rates with the current treatment duration of 48 weeks, whereas patients achieving a partial EVR have lower rates of SVR and could benefit from treatment intensification to 72 weeks. Here, we discuss the importance of baseline predictors of response and the emerging concept of response-guided therapy in genotype 1 and 4 patients.

Mericitabine and Either Boceprevir or Telaprevir in Combination with Peginterferon Alfa-2a plus Ribavirin for Patients with Chronic Hepatitis C Genotype 1 Infection and Prior Null Response: The Randomized DYNAMO 1 and DYNAMO 2 Studies.

UNLABELLED: Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-log10 reduction in HCV RNA by treatment week 12) to peginterferon/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60-70% in DYNAMO 1 and of 71-96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI. TRIAL REGISTRATION: ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390.

Identifying HCV genotype 1 patients at risk of relapse.

OBJECTIVE: The objective of this analysis was to identify predictors of relapse in genotype 1 patients after 48 weeks of treatment with peginterferon plus ribavirin. METHODS: Retrospective analysis of data from treatment-naive genotype 1 patients with an end-of-treatment response after 48 weeks of treatment with peginterferon alpha-2a plus ribavirin 1000/1200 mg/day in the Canadian Pegasys Expanded Access Program. RESULTS: Among treatment-naive genotype 1 patients with an end-of-treatment response (n = 432), the sustained virological response status was known for 405 individuals (sustained virological response n = 328, 81%; relapse n = 77, 19%). Early virological response rates at week 12 were similar in relapsers (98.7%) and sustained responders (98.5%). More relapsers (12 of 77, 15.6%) than sustained responders (15 of 328, 4.6%) had quantifiable hepatitis C virus (HCV) RNA (>or=600 IU/ml) at week 12 and, among these patients, mean and maximum HCV RNA levels were higher in relapsers, although the median values were similar. Factors significantly associated with relapse in the multiple logistic regression analysis include older age (odds ratio: 1.48 per decade, 95% confidence interval: 1.06-2.07; P = 0.023), Caucasian ethnicity (odds ratio: 3.23, confidence interval: 1.25-8.33; P = 0.016), higher baseline serum HCV RNA level (P = 0.005), the drop in HCV RNA between baseline and week 12 (P = 0.026), and the interaction between baseline HCV RNA level and the decrease in HCV RNA between baseline and week 12 (P = 0.032). CONCLUSION: Older age, Caucasian ethnicity, and high baseline HCV RNA level, and a smaller decrease in HCV RNA between baseline and week 12 predict a relapse in genotype 1 patients.

Prognostic factors and early predictability of sustained viral response with peginterferon alfa-2a (40KD).

BACKGROUND/AIMS: Baseline factors and early decline in serum hepatitis C virus RNA are predictive of sustained virological response to interferon therapy in patients with chronic hepatitis C. We evaluated the prognostic value of baseline factors and early viral RNA among patients treated with peginterferon alfa-2a (40KD). METHODS: Data were pooled from three randomized trials involving 814 patients treated with peginterferon alfa-2a (40KD) (90, 135, or 180 mirog). Stepwise and multiple logistic regression identified independent baseline factors associated with response. Receiver operating characteristic curves for both absolute values and log(10) decline in viral RNA at 4, 8, 12 and 24 weeks of therapy were created. RESULTS: Independent prognostic factors for sustained virological response included viral genotype non-1, low pretreatment viral load, age (<40 years), no cirrhosis and body weight (<85 kg). In addition, alanine aminotransferase quotient (>3) and histological activity index score (>10) were also independently prognostic. Receiver operating characteristic curves showed that detectable or less than 2-log(10) decline in viral RNA at week 12 predicted sustained virological non-response (negative predictive value is 98%) . CONCLUSIONS: In patients with chronic hepatitis C treated with peginterferon alfa-2a (40KD), the decision to continue or stop treatment can be made as early as week 12.